Activin-actrii antagonists and uses for treating anemia
AssigneesCelgene Corporation, Acceleron Pharma Inc.
InventorsKenneth M. Attie, Christopher Rovaldi, Abderrahmane Laadem
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Abstract
Provided herein are methods for the treatment in a subject of anemia, anemia requiring RBC transfusion, low or intermediate-1-risk myelodysplastic syndromes (MDS), and/or non-proliferative chronic myelomonocytic leukemia (CMML) in any mammals wherein the methods comprise administration of Activin-ActRII signaling inhibitors to a subject in need of the treatment.
Claims117
A method of treating a blood-related disorder in a subject, comprising
- (a) determining a percentage of erythroblasts in the subject that are ring sideroblasts;
- and
- (b) administering a pharmaceutically effective dose of an ActRII signaling inhibitor of between 0.1 mg/kg and 2.0 mg/kg to the subject if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of erythroblasts in the subject are ring sideroblasts.
A method of treating a blood-related disorder in a subject, comprising administering to the subject an activin receptor type II (ActRII) signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts;
- and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor;
- wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.
A method of treating anemia in a subject, comprising administering to the subject an activin receptor type II (ActRII) signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts;
- and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor;
- wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.
A method for treating MDS in a subject, comprising administering to the subject an ActRII signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts;
- and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor;
- wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.
A method for treating non-proliferative CMML in a subject, comprising administering to the subject an ActRII signaling inhibitor at a pharmaceutically effective dose and for a period of time to achieve (i) a long-term reduction in a percentage of erythroblasts in the subject that are ring sideroblasts as compared to an initial percentage of erythroblasts in the subject that are ring sideroblasts;
- and/or (ii) a long-term increase in hemoglobin level in the subject as compared to the hemoglobin level in the subject a period of time prior to administering to the subject an initial dose of the ActRII signaling inhibitor;
- wherein the pharmaceutically effective dose is between 0.1 mg/kg and 2.0 mg/kg, and wherein the initial percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%.
The method of any one of the preceding claims, wherein the ActRII signaling inhibitor is administered once every three weeks.
The method of any one of the preceding claims, wherein the ActRII signaling inhibitor is administered via injection.
The method of any one of the preceding claims, wherein the method further comprises determining an additional percentage of erythroblasts in the subject that are ring sideroblasts 6, 12, 18, and/or 24 months after the period of time of ActRII signaling inhibitor administration.
The method of any one of the preceding claims, wherein the percentage of erythroblasts in the subject that are ring sideroblasts is determined by Prussian blue staining.
The method of any one of the preceding claims, wherein the method further comprises determining an additional hemoglobin level in the subject 6, 12, 18, and/or 24 months after the period of time of ActRII signaling inhibitor administration.
A method for treating a blood-related disorder in a subject, wherein the method comprises:
- (a) determining the percentage of erythroblasts in the subject that are ring sideroblasts;
- and
- (b) (i) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a short period of time if the percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, or (ii) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a long period of time if the percentage of erythroblasts in the subject that are ring sideroblasts is less than 10%.
A method for treating anemia in a subject, wherein the method comprises:
- (a) determining a first percentage of erythroblasts in the subject that are ring sideroblasts;
- and
- (b) (i) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a short period of time if the first percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, or (ii) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a long period of time if the percentage of erythroblasts in the subject that are ring sideroblasts is less than 10%.
A method for treating MDS in a subject, wherein the method comprises:
- (a) determining a first percentage of erythroblasts in the subject that are ring sideroblasts;
- and
- (b) (i) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a short period of time if the first percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, or (ii) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a long period of time if the percentage of erythroblasts in the subject that are ring sideroblasts is less than 10%.
A method for treating non-proliferative CMML in a subject, wherein the method comprises:
- (a) determining a first percentage of erythroblasts in the subject that are ring sideroblasts;
- and
- (b) (i) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a short period of time if the first percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%, or (ii) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg for a long period of time if the percentage of erythroblasts in the subject that are ring sideroblasts is less than 10%.
A method of treating a blood-related disorder in a subject, wherein the method comprises:
- (a) determining that the subject has a percentage of erythroblasts in the subject that are ring sideroblasts of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (b) administering to the subject an initial dose of between 0.1 mg/kg and 2.0 mg/kg of an ActRII signaling inhibitor;
- (c) determining a second percentage of erythroblasts in the subject that are ring sideroblasts after a period of time;
- and
- (d) optionally administering to the subject an adjusted dose of the ActRII signaling inhibitor.
A method of treating anemia in a subject, wherein the method comprises:
- (a) determining that the subject has a percentage of erythroblasts in the subject that are ring sideroblasts of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (b) administering to the subject an initial dose of between 0.1 mg/kg and 2.0 mg/kg of an ActRII signaling inhibitor;
- (c) determining a second percentage of erythroblasts in the subject that are ring sideroblasts after a period of time;
- and
- (d) optionally administering to the subject an adjusted dose of the ActRII signaling inhibitor.
A method of treating MDS in a subject, wherein the method comprises:
- (a) determining that the subject has a percentage of erythroblasts in the subject that are ring sideroblasts of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (b) administering to the subject an initial dose of between 0.1 mg/kg and 2.0 mg/kg of an ActRII signaling inhibitor;
- (c) determining a second percentage of erythroblasts in the subject that are ring sideroblasts after a period of time;
- and
- (d) optionally administering to the subject an adjusted dose of the ActRII signaling inhibitor.
A method of treating non-proliferative chronic myelomonocytic leukemia (CMML) in a subject, wherein the method comprises:
- (a) determining that the subject has a percentage of erythroblasts in the subject that are ring sideroblasts of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (b) administering to the subject an initial dose of between 0.1 mg/kg and 2.0 mg/kg of an ActRII signaling inhibitor;
- (c) determining a second percentage of erythroblasts in the subject that are ring sideroblasts after a period of time;
- and
- (d) optionally administering to the subject an adjusted dose of the ActRII signaling inhibitor.
A method for treating a blood-related disorder in a subject, wherein the method comprises:
- (a) determining the percentage of erythroblasts in the subject that are ring sideroblasts;
- (b) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg if the percentage of erythroblasts in the subject that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (c) determining a level of hemoglobin in the subject after ActRII signaling inhibitor is administered to the subject;
- and
- (d) discontinuing administration of the ActRII signaling inhibitor to the subject if the level of hemoglobin in the subject is at least 11 g/dL.
A method for treating anemia in a subject, wherein the method comprises:
- (a) determining the percentage of erythroblasts in the subject that are ring sideroblasts;
- (b) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg if the percentage of erythroblasts in the subject that are ring sideroblasts in the subject is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (c) determining a level of hemoglobin in the subject after ActRII signaling inhibitor is administered to the subject;
- and
- (d) discontinuing administration of the ActRII signaling inhibitor to the subject if the level of hemoglobin in the subject is at least 11 g/dL.
A method for treating MDS in a subject, wherein the method comprises:
- (a) determining the percentage of erythroblasts in the subject that are ring sideroblasts;
- (b) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg if the percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (c) determining a level of hemoglobin in the subject after ActRII signaling inhibitor is administered to the subject;
- and
- (d) discontinuing administration of the ActRII signaling inhibitor to the subject if the level of hemoglobin in the subject is at least 11 g/dL.
A method for treating non-proliferative CMML in a subject, wherein the method comprises:
- (a) determining the percentage of erythroblasts in the subject that are ring sideroblasts;
- (b) administering an ActRII signaling inhibitor to the subject at a pharmaceutically effective dose of between 0.1 mg/kg and 2.0 mg/kg if the percentage of erythroblasts in the subject that are ring sideroblasts is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or at least 20%;
- (c) determining a level of hemoglobin in the subject after ActRII signaling inhibitor is administered to the subject;
- and
- (d) discontinuing administration of the ActRII signaling inhibitor to the subject if the level of hemoglobin in the subject is at least 11 g/dL.
A method of promoting erythropoiesis in a subject having a blood-related disorder, the method comprising:
- (a) determining a percentage of erythroblasts in the subject that are ring sideroblasts;
- (b) administering a pharmaceutically effective dose of an ActRII signaling inhibitor to the subject for a first period of time;
- (c) after the first period of time, if the percentage of erythroblasts in the subject that are ring sideroblasts in step (a) had been above 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, reducing the dose of the ActRII signaling inhibitor administered to the subject, reducing the frequency of administration of the ActRII signaling inhibitor to the subject, or discontinuing administering of the ActRII signaling inhibitor.
The method of any one of the preceding claims, wherein the subject has an increased likelihood of achieving normalization of one or more hematological parameters if at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of erythroblasts in the subject are ring sideroblasts.
A method for increasing the level of neutrophils in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signaling inhibitor.
A method for increasing the level of platelets in a subject, comprising administering to the subject a pharmaceutically effective dose of an activin receptor type II (ActRII) signaling inhibitor.
The method of any one of the previous claims, wherein the ActRII signaling inhibitor is a polypeptide comprising an amino acid sequence selected from the group consisting of:
- (a) 90% identical to SEQ ID NO:2;
- (b) 95% identical to SEQ ID NO:2;
- (c) 98% identical to SEQ ID NO:2;
- (d) SEQ ID NO:2;
- (e) 90% identical to SEQ ID NO:3;
- (f) 95% identical to SEQ ID NO:3;
- (g) 98% identical to SEQ ID NO:3;
- (h) SEQ ID NO:3;
- (i) 90% identical to SEQ ID NO:6;
- (j) 95% identical to SEQ ID NO:6;
- (k) 98% identical to SEQ ID NO:6;
- (l) SEQ ID NO:6;
- (m) 90% identical to SEQ ID NO:7;
- (n) 95% identical to SEQ ID NO:7;
- (o) 98% identical to SEQ ID NO:7;
- (p) SEQ ID NO:7;
- (q) 90% identical to SEQ ID NO:12;
- (r) 95% identical to SEQ ID NO:12;
- (s) 98% identical to SEQ ID NO:12;
- (t) SEQ ID NO:12;
- (u) 90% identical to SEQ ID NO:17;
- (v) 95% identical to SEQ ID NO:17;
- (w) 98% identical to SEQ ID NO:17;
- (x) SEQ ID NO:17;
- (y) 90% identical to SEQ ID NO:20;
- (z) 95% identical to SEQ ID NO:20;
- (aa) 98% identical to SEQ ID NO:20;
- (bb) SEQ ID NO:20;
- (cc) 90% identical to SEQ ID NO:21;
- (dd) 95% identical to SEQ ID NO:21;
- (ee) 98% identical to SEQ ID NO:21;
- (ff) SEQ ID NO:21;
- (gg) 90% identical to SEQ ID NO:25;
- (hh) 95% identical to SEQ ID NO:25;
- (ii) 98% identical to SEQ ID NO:25;
- and
- (jj) SEQ ID NO:25.
The method of any of the preceding claims, wherein the ActRII signaling inhibitor is an ActRIIA signaling inhibitor.
The method of claim any one of the previous claims, wherein the ActRII signaling inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:7.
The method of any one of the previous claims, wherein the subject is human.
Dependencies are inferred from the claim text.